The field of the invention relates to compounds that inhibit mitogen-activated protein kinase interacting kinases 1 and/or 2 (Mnk1 and/or Mnk2). In particular, the field of the invention relates to substituted N-heterocyclic aromatic-based compounds as inhibitors of Mnk1 and/or Mnk2 for the treatment for the treatment of diseases and disorders associated with Mnk1 and/or Mnk2, including cell proliferative diseases or disorders (e.g., cancers such as AML), diabetes, autism, and fragile X syndrome.
While treatment options have improved in recent years, cancer remains the second leading cause of death in the United States. Many cancers lack effective treatments and have poor long-term prognoses. In particular, acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence increases with age. Although AML is a relatively rare disease, accounting for only ˜1% of cancer deaths in the United States, the incidence of AML is expected to increase as the U.S. population ages. As an acute leukemia, AML progresses rapidly and is typically fatal within weeks or months if left untreated.
Here, as part of an effort to discover and evaluate new small molecules that have the potential for treating human cancer, in particular hematological malignancies such as AML, we have identified a series of so-called substituted N-heterocyclic aromatic-based compounds that display potent in vitro cytotoxicity against AML cells, involving targeting an enzyme in the cell called Mnk. Compound analogs have been synthesized and tested to generate robust structure-activity relationships based on multiple sites of diversification. Lead compounds possess excellent profiles as potential therapeutics based on a variety of physiochemical properties. These new compounds therefore hold promise as new potential treatments for cancers such as AML and other proliferative diseases.
Because the compounds disclosed herein are shown to be inhibitors of Mnk, these compounds may be useful for treating other diseases and disorders associated with Mnk-activity. Mnk kinase phosphorylates eIF4E, whose activity has been implicated in disorders such as diabetes (U.S. Published Application No. 20090170095 A1), autism (Nature 493, 371-377), and fragile X syndrome (Nature Neuroscience 16, 1530-1536 (2013)).